Active Surveillance and Chantix: Smoking Out Adverse Events

There are lots of “top” lists out there. Maxim magazine has its annual Hot 100 awards. David Letterman has his weekly Top Ten contest. But if you’re a pharmaceutical company, there’s one list you don’t want to be on: the Institute of Safe Medication Practices’ list of most dangerous drugs.

That’s not actually the name of the list, but it might as well be. Officially, the list is called “Leading Suspect Drugs”—products with the most reports of serious adverse events in a given calendar quarter. And the most recent data, released by ISMP yesterday, has a new drug at the top: Pfizer’s varenicline (Chantix).

The idea that a product for smoking cessation would be considered that risky comes as a bit of a shock, especially when the other drugs on ISMP’s list are for seriously ill patients and tend to have “black box” warnings: interferon, Enbrel, Remicade, fentanyl and oxycodone. By comparison, Chantix is approved for use in healthy people to stop smoking. Labeling includes a bolded, but not boxed, warning.

But if Chantix’ ranking comes as a surprise, it shouldn’t. Indeed, Chantix has been steadily climbing to the top spot on ISMP’s list, based in large part on an increased incidence of psychiatric adverse events. FDA has already issued two advisories on events like depression and suicide; we wrote that story in the latest issue of The RPM Report, which you can access here.

Chantix first appeared on ISMP’s radar screen in the fourth quarter of 2006 as one of a small group of drugs that accounted for 100 or more reports of serious injury in a calendar quarter. By the second quarter of 2007, Chantix ranked third among all drugs in the US, and by the fourth quarter of 2007, it “accounted for more reports of serious drug adverse events in the United States than any other drug,” ISMP says. Given those results, ISMP was compelled to publish a report on the “strong signal.”

The accuracy of that signal—and whether Chantix truly belongs on the top of ISMP’s list—deserves to be questioned a bit. Adverse event reports can be driven by publicity about the safety of a product, and there has been plenty of buzz about Chantix, especially on psychiatric adverse events. FDA’s “early communication” on Chantix in November 2007 could have led to an increased number of reports. ISMP would debate that point, arguing that it would take longer for reports to appear in the FDA system.

Regardless, the real lesson here is on the consequences of active surveillance, and what happens when an independent group like ISMP dives into adverse event data. In the case of Chantix, it has the potential to take down a blockbuster. Bernstein Research analyst Tim Anderson cut in half his worldwide sales expectations on the news out of ISMP this week. That’s not small change: “Our assessment is that consensus forecasts in 2012 may be too high by as much as $500 million-$1 billion,” Anderson says.

Indeed, ISMP’s fishing expedition is exactly why the pharmaceutical industry needs to get behind an official active surveillance program—a neutral referee in the fast-paced, increasingly public game of post-marketing safety. Luckily, FDA is about to implement one. Today, HHS and FDA released more details about the Sentinel System, an active surveillance program that will use Medicare Part D claims to monitor post-marketing safety.

For industry, that may seem scary, given the potential for false-positives. But having a strong organization that can take a leadership role in post-marketing safety is a good thing. As Center for Drug Evaluation & Research director Janet Woodcock put it, FDA will use Sentinel to develop “best practices” for active surveillance—scientifically agreed-upon analytical methods, so that
“we can all agree what the results mean.”

The alternative—random groups and researchers using disparate databases to analyze adverse event data—is much less appealing. FDA's Woodcock acknowledges that Sentinel will lead to more warnings on products, and that may well be the near-term impact. But with any luck, Sentinel will create a lot less chaos over the long term—and fewer primary care blockbusters topping ISMP's “suspect drugs” list.

Stewie image courtesy of Flickr user speakfreegirl via a creative commons license.